The multi-gene family of proteins called connexins form intercellular gap junctions that directly mediate signaling between adjacent cells. These cell-cell channels consist of two hemichannels or so-called connexons from adjacent cells. In addition to forming gap junctions, some members of the connexin family can also function as transmembrane ion channels in the undocked state. Thus, connexins can participate in mediating signaling across the plasma membrane as well as between cells. Both cell-cell channels and hemichannels formed by connexins play a wide variety of roles in a number of different cell types and tissues, as highlighted by numerous studies using genetic and molecular approaches. Connexin channels have also been proposed as new and promising pharmacological targets in the treatment of epilepsy, cardiac arrhythmia, cancer, stroke, essential tremor, and in reducing the extent of cell death following ischemia. However, progress in the identification and characterization of specific and high-affinity inhibitors of these channels, which would greatly assist in the investigation of their physiological and pathophysiological roles, has been unfortunately slow. With the goal of identifying new classes of drugs that inhibit connexin channels, we initiated a collaboration with Dr. Heike Wulff at UC Davis in July 2006, whose laboratory specializes in the design of small molecule ion channel modulators. Through screening of a small number of compounds from Dr. Wulff's libraries enriched in ion channel modulators we have already identified four new small molecule chemotypes that inhibit connexin channels In this grant proposal, we propose to extensively probe the SAR of these molecules using a classical medicinal chemistry approach with the ultimate goal of developing a high-affinity, specific inhibitor(s) of connexin channels. PUBLIC HEALTH RELEVANCE: Proteins called connexins play a wide variety of roles in human physiology and disease. However there are no pharmacological tools to evaluate their role in human biology or to determine their therapeutic utility in prevention/cure of certain types of diseases. Proposed studies are aimed at the development of pharmacological agents for this class of channels.